Our overall aim is to develop a novel approach to the prevention and therapy of Mycobacterium tuberculosis infections. We have generated murine monoclonal antibodies that recognize surface antigens of M. tuberculosis and identified one of them as protective in a mouse model. The aims of this project are: 1) to define the relationship between antibody isotype and biological efficacy; 2) to establish the mechanism(s) of antibody-mediated protection (or enhancement) in M. tuberculosis infection; 3) to study the interaction of monoclonal antibodies with cell-mediated immunity. The experimental approach will be: to generate switch variants of the protective monoclonal antibody; test the ability of these reagents to prolong survival and decrease organ mycobacterial burden in a mouse model; study the mechanisms by which they exert their biological functions using in-vivo and in-vitro studies; and study their interaction with cell-mediated immunity using in-vivo and in-vitro studies. This study will help us understand the structural characteristics required for useful antibodies to M. tuberculosis.